Influence of risedronate on orthodontic tooth movement in rodents: a systematic review and case report

ABSTRACT Introduction: Bisphosphonates have an inhibitory impact on osteoclastic activity, reducing bone resorption. However, the influence of risedronate on tooth movement is not well-defined. Objective: This systematic review assessed the effect of risedronate intake on orthodontic tooth movement. A case report was also provided. Methods: Two independent reviewers searched six databases (PubMed, Web of Science, Ovid, Lilacs, Scopus, and Open Grey). The searches were carried out in April/2020, and an update was set in place in June/2023. Therefore, the searches considered a timeline from the databases’ inception date until June/2023, with no publication date and/or language restrictions. The clinical question focused on evaluating the orthodontic tooth movement and relapse movement (Outcome) in animals (Population) exposed to risedronate (Exposure), compared to control groups (Comparison). The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were applied, and the protocol was registered in PROSPERO (CRD42020168581). The risk of bias was determined using the Systematic Review Centre for Laboratory Animal Experimentation protocol (SYRCLE). Results: Two studies in rats and one in guinea pigs were included in the systematic review. The studies reported a decrease in orthodontic tooth movement, a reduction in the relapse movement, and a reduced number of positive tartrate-resistant acid phosphatase (TRAP) cells, with a significantly reduced number of bone gaps after the administration of risedronate in rats. A case report illustrated the effects of risedronate administration in one patient. Conclusion: Based on the systematic review, risedronate seems to impair orthodontic tooth movement and relapse due to a decrease in bone resorption cells.


INTRODUCTION
Orthodontic treatment can enhance the quality of life of individuals and improve gnathic function, providing better occlusion and esthetics. 1Tooth movement occurs through bone remodeling, 2 which is only possible because of the sequential activity of osteoclasts (bone resorption) in areas of pressure, and osteoblasts (bone formation) in areas of tension. 2 Factors that affect tooth movement during orthodontic treatment have been widely studied, and the use of drugs that alter bone turnover, such as bisphosphonates, has been investigated. 3sphosphonates are anti-resorptive drugs used to treat or prevent bone disorders, such as osteoporosis. 4Their mechanism of action includes an inhibitory effect on osteoclastic activity, which consequently reduces bone resorption. 5,6sphosphonates are used for the treatment of several osseous disorders. 4,7The main subtypes of bisphosphonates are alendronate, ibandronate, risedronate, pamidronate, clodronate, and zoledronic acid.The risedronate acid, or risedronate, is a pyridinyl bisphosphonate with a specific indication for the treatment of osteoporosis and to prevent fractures in postmenopausal women. 8,9ospective studies have demonstrated that risedronate reduces the risk of vertebral, non-vertebral, and hip fractures. 5,6,9Although the drug may be associated with bisphosphonate-related osteonecrosis of the jaw in women, 10 risedronate has a marked effect in reducing the prevalence of periapical lesions, 11 as well as in increasing bone density in rats with glucocorticoid-induced osteoporosis. 12The effects of risedronate on mechanically-induced tooth movement, however, have not been well-defined, due to the absence of studies in human subjects and methodological discrepancies in experimental models.The present study aimed to compile, in a systematic review, data published specifically about risedronate, to verify its effects on orthodontic tooth movement.A case report of a postmenopausal patient who took risedronate before and while performing the orthodontic treatment is also provided.
The present data associated with the clinical case may alert orthodontists about the need for rigorous anamnesis and clinical examination before orthodontic treatment, and carefully consider all medications used by their patients that may alter bone remodeling and, consequently, orthodontic treatment.

ELIGIBILITY CRITERIA
The question proposed was "Does the systemic or local administration of risedronate affect orthodontic tooth movement in animals?".Eligibility criteria included original studies that assessed orthodontic tooth movement and relapse movement in animals who were undergoing treatment with risedronate (administered orally or injected, with a systemic or local effect), and Dental Press J Orthod.2023;28(6):e2322280 the administration of risedronate after treatment, in order to assess factors related to stability.A control group was required as inclusion criteria.All treatment schedules, frequencies, and dosages were eligible for inclusion.Case studies, case series, comments, letters to the editor, narrative reviews, and studies that evaluated histological or cytological aspects, but did not evaluate tooth movement, were excluded.The following PECO question was applied:

SOURCES OF INFORMATION AND SEARCH STRATEGIES
The following electronic databases were used: PubMed, Web of Science, Ovid, Lilacs, and Scopus.A search in Google Scholar and a search of the gray literature in Open Gray were also conducted.
No publication dates or language restrictions were applied.
The searches were carried out in April/2020, and an update was set in place in June/2023.Therefore, the searches considered a timeline from the databases' inception date until June/2023.

The complete search strategy was based on the following search
-pyridinyl)-1-hydroxyethylidenebisphosphonate AND "Tooth Movement Technique" OR "Tooth Movement Techniques" OR "Orthodontic Tooth Movement" OR "Orthodontic Tooth Movements" OR "Tooth Uprighting" OR "Tooth Uprightings" OR "Minor Tooth Movement" OR "Minor Tooth Movements" OR "Tooth Intrusion" OR "Tooth Intrusions" OR "Tooth Depression" OR "Tooth Depressions" OR "Orthodontic Treatment" OR "Orthodontic Therapy" OR "Orthodontic Movement" OR "Tooth Movement"

SELECTION OF STUDIES
Two authors independently reviewed the references retrieved in the searches, examining the titles and/or abstracts of the studies.When the abstracts of the articles were unavailable or did not provide sufficient information to reach a decision on inclusion or exclusion, the full text was then assessed.References that met the eligibility criteria were included.
Any disagreements between authors about the eligibility of specific studies were resolved through a discussion with a third reviewer.

DATA EXTRACTION AND ITEMS EXTRACTED
Data were extracted and incorporated into three tables in Excel ® .The following data were extracted: authors (year, country), study design, study subjects, mean age, study groups, study duration, and primary assessment methods.
The data also included all of the characteristics of the experiments, such as duration, applied force, other displacements, and statistical analysis, and information on the results and conclusions of the included studies.Data extraction was performed by two authors of the systematic review, independently, and the discrepancies were identified and resolved through discussion.

RISK OF BIAS ASSESSMENT
Two independent authors used the SYRCLE risk of bias tool 13 to assess the risk of bias.Any disagreement between the two authors was resolved with a third party.

EFFECT MEASURE
Information on any effect measure concerning the influence of risedronate on orthodontic tooth movement in rodents was collected.

SYNTHESIS OF RESULTS
Data of the included studies were heterogeneous, and any attempt to perform a quantitative analysis was unfeasible in the period of April/2020 to June/2023.

STUDY SELECTION
The database searches retrieved 443 references.After the removal of 81 duplicate records, 362 titles and/or abstracts were examined.Three hundred fifty-seven studies were excluded due to not meeting the eligibility criteria.Five studies were selected for full-text evaluation.Two studies were excluded because only histological or cytological aspects had been evaluated.Thus, three studies with animals were included in this systematic review (Adachi et al. 14 , 1994; Wu et al. 15 , 2019; Utari et al. 16 , 2021).
A flow diagram of study selection is displayed in Figure 1.

STUDY CHARACTERISTICS
All included studies [14][15][16] aimed to investigate the effect of risedronate on orthodontic tooth movement and relapse movement in animals (rats and guinea pigs).Adachi et al. 14   The risedronate solution was injected into the sub-periosteum region, adjacent to the left upper first molar.The right first molar served as a control, with the injection of 0.9% NaCl solution.
In experiment two, the upper right and left first molars were submitted to orthodontic forces for three weeks.The spring was removed, and the administration of risedronate was started (relapse movement).Wu et al. 15 used 45 female rats (Sprague-Dawley) distributed into three groups: sham (treated with saline), bilaterally ovariectomized rats (OVX, treated with saline), and OVX + intraperitoneally risedronate rats.One month after surgery, a mesial force was applied on the left upper first molar using a nickel-titanium (NiTi) coil.Utari et al. 16 used an orthodontic appliance to induce a distal orthodontic tooth movement of the lower incisors of guinea pigs (n = 75) up to ±3 mm in length.Risedronate was added to gelatin hydrogel to obtain a semisolid controlled release, and the Bis-CR250 (250 mmol/L) and Bis-CR500 (500 mmol/L) groups (n = 25 per group) were compared to a control group (Bis-CR000, n = 25).Subsequently, risedronate was applied in an intrasulcular manner into the mesial subperiosteal area every three days.After 14 days of stabilization, the apparatus was removed, and the relapse distance between incisors and the osteoclast number with TRAP staining at 0, 3, 7, 14, and 21 days were measured (Table 1).
Group A: 3 weeks.Group A2: Risedronate-treated side had decreased osteoclast count per area at the periods of 3, 7 and 14 days.Decreased percentage of the size of the lacunae and resorptive area on the risedronate-injected side.

Group B1:
The relapse of the tooth on the risedronate-injected side was significantly less than control.The percent inhibition (b/a x 100) was 96.1%, 79.8%, 73.7%, and 56.7% of the control side at concentrations of 0, 125, 250, and 500 µmol/L, respectively.Group B2: Except on day 14, risedronate had decreased number of osteoclasts in all time points.Sizes of active bone-resorptive lacunae could not be determined.osteoclast were abundant along the alveolar bone in Bis-CR000 but decreased in the Bis-CR250 and Bis-CR500 groups.

STUDY CHARACTERISTICS RELEVANT TO THE APPLICATION OF ORTHODONTIC FORCE
In the study conducted by Adachi et al.  2).Utari et al. 16 employed a NiTi open coil spring inserted between the lower incisors using a 0.1 mm stainless steel wire to produce a 0.25 to 1.30 N magnitude of force to the teeth.The spring coil was replaced with a new coil after the incisors reached a ±3-mm inter-incisor distance, which was maintained for 14 days as a stabilization period, at which time risedronate was applied locally (Table 2).

STUDY CHARACTERISTICS RELEVANT TO RISEDRONATE ADMINISTRATION
The administration volume of risedronate used by Adachi et al. 14 was 50 μL of a solution at concentrations of 0 (0.9% NaCl), 125, 250, or 500 µmol/L.The results suggested that the topical application of risedronate may be useful in anchoring and retaining teeth in orthodontic treatment.In the study of Wu et al. 15 , risedronate was diluted in saline and administered  ing that a dose of 500 mmol/L was more effective (Table 2).

MAIN STUDY OUTCOME VARIABLES
According to Adachi et al. 14 , the topical administration of risedronate inhibited relapse movement in a dose-dependent manner.Wu et al. 15 showed decreased orthodontic tooth movement and a reduced number of osteoclasts in the OVX + risedronate group, when compared to the OVX group (Table 3).Utari et al. 16 verified that topically administered risedronate gelatin hydrogel is highly effective in decreasing the tooth relapse movement and the number of osteoclasts (Table 3).significantly less than that on the control side.
The inhibitory effect was dose-depedent.* The relapse of the tooth on the risedronate injected side was significantly less than that on the control side.The inhibitory effect of risedronate was again dose-dependent.At 3 days, there was no statistically difference between control and experimental teeth although had rapidly relapsed about 0.2 mm and 0.23 mm, respectively.At day 14, there was significant difference; and at day 21, the control teeth had relapsed an average of 0.44 mm, whereas experimental teeth had relapsed only 0.24 mm.
No histological differences on the tension were observed between the control side and risedronate-injected side during the experimental period.However, quantitative examinations of bone formation, such as a study of bone formation rates, will be required to determine the precise effect of risedronate on alveolar bone formation incident to tooth movement.

Wu et al. 15 (2019, China)
* The number of TRAP-positive cells in the ovariectomy group was higher than that in the sham group (P < 0.01 on days 3, 7 and 14).* The number of TRAP-positive cells was reduced after the injection of risedronate into the ovariectomized rats (P < 0.05 on days 3, 7 and 14).* The number of TRAP-positive cells in the ovariectomy + risedronate group was higher than that in the sham group (P < 0.05 on days 3, 7 and 14).
* The orthodontic tooth movement in the ovariectomy group was faster than in the sham group (P < 0.01 on days 3, 7 and 14).* Injection of risedronate into the ovariectomized rats decreased the orthodontic tooth movement velocity (P < 0.01 on days 3 and 14, P < 0.05 on day 7).
Risedronate can inhibit orthodontic tooth movement in ovariectomized rats and may function by regulating the RANK/ RANK ligand/osteoprotegerin pathway.
* Both Bis-CR250 and Bis-CR500 had no detectable release before 1 hour of immersion.* Osteoclasts were abundant along alveolar bone in Bis-CR000, but decreased in the Bis-CR250 and Bis-CR500 groups, showing the inhibition of osteoclasts activity.
* The control had the highest relapse rate at days 14 and 21.* There was a significantly less relapse movement in the treatment group at days 14 and 21, compared to control.* Bis-CR500 inhibited the relapse movement more effectively than Bis-CR250 on day 21, indicating a dose dependency in the bisphosphonate hydrogel application.
Topically administered bisphosphonate risedronate with gelatin hydrogel effectively decreases the relapse 7 days after the tooth stabilization period in a dose-dependent manner.
The developed gelatin hydrogel system is able to deliver the risedronate to a targeted area in a controlled manner and provide local effects, which is useful in orthodontic practice

RISK OF BIAS ASSESSMENT
The three articles included in the present study [14][15][16] presented a low risk of bias for sequence generation, baseline characteristics, and incomplete outcome data.
5][16] The risk of bias was unclear for random housing and blinding of trial caregivers/researchers in findings from both Adachi et al. 14 and Utari et al. 16 studies, and low in findings from of Wu et al. 15 study.By contrast, the risk of bias was low for random outcome assessment and the blinding of outcome assessors in findings from both Adachi et al. 14 and Wu et al. 15 studies, and unclear in findings from Utari et al. 16 study (Table 4).High risk of bias = The study does not meet the requirement.Low risk of bias = The study meets the requirement.Unclear risk of bias = It is unclear whether the study meets the requirement.

CASE REPORT
A 55-year-old female patient with a diagnosis of osteoporosis was referred to the Orthodontic Clinic at the Federal University of Minas Gerais (Brazil) to undergo treatment with fixed appliances.Her main complaint was the protrusion of her upper anterior teeth and overjet (Suppl.Figs 1 and 2).During anamnesis, the patient reported taking Actonel 150 mg (risedronate) once a month and a calcium supplement daily.She also reported taking Angeliq (drospirenone 2 mg and estradiol 1 mg) to treat the symptoms of menopause, and simvastatin 20 mg to control cholesterol levels, both once a day.All medications had been taken for six years prior to this study.The treatment plan consisted of fixed appliance bonding, alignment, and leveling; the extraction of two upper first premolars; and en-masse retraction of the upper anterior teeth for space closure.Two years after the beginning of orthodontic treatment, the en-masse retraction was progressing at a slow rate.The orthodontist, who was aware of the intake of bisphosphonate by the patient to treat osteoporosis, requested new orthodontic exams (intraoral and extraoral photographs and radiographic exams), in order to have an overview of treatment progress (Suppl.Fig. 3) and to monitor root resorption (Fig. 2B).
The panoramic radiograph revealed an increased mesial inclination

DISCUSSION
This systematic review revealed that risedronate impaired orthodontic movement can reduce the number of osteoclasts and the size of resorption gaps in rats.The radiographic analysis of the patient from the aforementioned case report also showed that the chronic intake of risedronate increased the density of both the maxillary and the mandibular periradicular bone, thus impairing orthodontic tooth movement.
8][19] Bisphosphonates have an inhibitory effect on bone resorption and are successfully administered for the treatment of osseous disorders, such as osteoporosis. 9,18,20Even though the action of bisphosphonate is generally well described in the literature and the effects in human subjects have also been documented, [21][22][23] studies that specifically evaluate risedronate intake and its impact on orthodontic tooth movement in humans are scarce.Although the results from this study are from animal research, and should thus be viewed with caution, the clinician should nevertheless be aware of the effects of risedronate during alveolar bone remodeling.
In this sense, this systematic review in animals associated with the clinical case is of particular relevance.This is the first systematic review that evaluates the association of the use of risedronate with orthodontic tooth movement, tooth relapse, and the number of osteoclasts in animals.
5][16] The identified studies were performed exclusively with animals, and no studies were found that assessed orthodontic tooth movement and risedronate in humans.Although the design and sample size of the three included studies were different, the effect of the medication was similar in all studies.
The data obtained in the selected studies demonstrated that the administration of risedronate directly interferes in orthodontic movement 14,15 and in the number of osteoclastic cells, [14][15][16] which may result in prolonged treatment time and tooth relapse movement, 14,16 with increased retentive effects.In 1994, Adachi et al. 14 experimentally showed that risedronate reduced the degree of tooth movement and tooth relapse movement in rats in a dose-dependent manner.These effects were also accompanied by a reduction in the number of osteoclasts.
Corroborating the findings of the present systematic review, in-vitro studies have shown that alendronate, 24 clodronate, 25 and risedronate 20 decreased osteoclast differentiation.
In addition, studies have already suggested the interference of bisphosphonates (but not risedronate) in human periodontal fibroblasts after mechanical load. 26,279][30] The studies included in the systematic review did not analyze the effects of risedronate on the osteoblasts, precluding any comparison between them.
In 1996, Igarashi et al. 31 investigated the effect of risedronate on root resorption in rats.Their findings showed that the side treated with risedronate showed significantly less root resorption on day 14 and day 21.The authors concluded that risedronate administered topically could prevent root resorption during orthodontic treatment.Though interesting, the outcomes of this study could not be included in our systematic review, since only histological parameters had been evaluated.
Results about tooth movement were unavailable.
Findings from Wu et al. 15  Regarding the effects of the different bisphosphonates on orthodontic movement, the study of Seifi et al., 32 in agreement with the results of the present systematic review, demonstrated that zoledronic acid (ZA) is a potent bisphosphonate that suppresses the role osteoclasts.In their study, ZA did not significantly inhibit orthodontic movement, but rather inhibited root resorption and angiogenesis in rats.Moreover, the continuous use of bisphosphonate suppressed osteoclast activity and preserved the alveolar bone around the roots in a mouse model.
After the discontinuation of bisphosphonate, the orthodontic tooth movement remained suppressed. 33sphosphonates have been used to inhibit bone fragility in patients with osteogenesis imperfecta (OI).Friedrich et al. 34  Based on the analysis of the radiographic periradicular alveolar bone, the bone cortex significantly increased after two years of orthodontic movement, and the effects of risedronate intake were more reactive on the mesial side of the teeth.The orthodontic tooth movement is a result of tension and compression, characterized by bone formation promoted by osteoblasts and resorption promoted by the osteoclasts, respectively. 2Risedronate increases osteoblast proliferation and differentiation, [28][29][30] which can explain the enhanced radiopacity of the mesial side where bone-forming cells prevailed.Therefore, the distal and apical regions were less affected.These findings could be explained by the differential physiological process of the alveolar bone remodeling during orthodontic tooth movement in each specific site. 41Moreover, it may be a mechanism of compensation of bone reabsorption on the distal side, since bisphosphonates have an effective inhibitory effect on osteoclasts. 18,30he more pronounced increase in the periradicular alveolar bone cortex of the mandible in comparison with the maxilla may be associated with the risedronate intake, and may also have followed the natural physiological aspects of those bones, with the mandible having a higher density than the maxilla. 42though there was impairment of tooth movement, a slight amount of root resorption was exhibited after the treatment.
These results contrast with those of Zymperdikas et al., 21,43

CONCLUSION
Based on the information compiled in rodents, it can be assumed that the rate of orthodontic tooth movement and tooth relapse movement may be affected by the administration of risedronate.

Miranda 5 Dental
RM, Fernandes JL, Santos MS, Jácome-Santos H, Milagres RMC, Pretti H, Abreu LG, Macari S -Influence of risedronate on orthodontic tooth movement in rodents: a systematic review and case report » P (Participants) = animals.» E (Exposure) = systematic or local administration of risedronate.» C (Comparison) = no systematic or local administration of risedronate.» O (Outcome) = tooth movement.

Figure 1 :
Figure 1: Flow diagram of study selection.
14 (1994), a 0.012-in NiTi standard and uniform expansion spring was designed and placed in the mouth of each animal between the right and left first molars.An initial force of 165 mN (Milli Newton) was applied on each side and was maintained in the oral cavity by its expansive force.Wu et al.15 also used a closed coil made of helical NiTi alloy, and the groups received 30 grams of force (measured by a dynamometer), adjusted by the length of the stainless steel bandage wires (Table
who verified a reduction in the prevalence of root resorption after the administration of bisphosphonates.Katz et al. 11  also revealed a reduced predominance of periapical lesions in osteoporotic patients, particularly among those who took risedronate.The strengths of the present review include the use of well-established guidelines in an attempt to reduce bias, as well as the exhaustive and comprehensive search strategy (April/2020 up to June/2023).The limitations arise from the number of articles, only three studies in rodents and none in humans; the type of information retrieved; and the means of risedronate administration.The results did not allow us to synthesize the data or perform meta-analyses.Furthermore, it should be emphasized that the information retrieved is not related to humans, a limitation that results in an overall downgrading of the quality of evidence regarding the human context.However, one should not forget that human studies analyzing the effect of risedronate upon orthodontic tooth movement are non-existent.Miranda RM, Fernandes JL, Santos MS, Jácome-Santos H, Milagres RMC, Pretti H, Abreu LG, Macari S -Influence of risedronate on orthodontic tooth movement in rodents: a systematic review and case report 29 Dental Press J Orthod.2023;28(6):e2322280The recommendation for further study is that future investigations, such as a clinical trial, should focus on patients using risedronate under orthodontic treatment.The clinical decision-making during orthodontic treatment need to be supported by scientific evidence.Orthodontists should perform a careful evaluation of the medical history of the patients undergoing treatment before beginning orthodontic therapy.Given the scarcity of animal studies and the absence of human studies evaluating the effect of risedronate upon orthodontic tooth movement, the randomized clinical trial is regarded as the basis for the evidence-based dentistry paradigm.This insight could be promising for future research in orthodontics.In summary, the results obtained from the systematic review and the case report indicate that risedronate administration causes impairment of orthodontic tooth movement with compromised clinical outcomes.Although these results are from animal studies and should thus be viewed with caution, the present data may assist oral health practitioners in tailoring specific treatment strategies for each user of this medication while undergoing orthodontic treatment.

Miranda RM, Fernandes JL, Santos MS, Jácome-Santos H, Milagres RMC, Pretti H, Abreu LG, Macari S - Influence of risedronate on orthodontic tooth movement in rodents: a systematic review and case report 7 Dental Press J Orthod. 2023;28(6):e2322280
Search strategies used in the databases.OR Tooth Movement Techniques OR Orthodontic Tooth Movement OR Orthodontic Tooth Movements OR Tooth Uprighting OR Tooth Uprightings OR Minor Tooth Movement OR Minor Tooth Movements OR Tooth Intrusion OR Tooth Intrusions OR Tooth Depression OR Tooth Depressions OR Orthodontic Treatment OR Orthodontic Therapy OR Orthodontic Movement OR Tooth Movement OR "Orthodontic Tooth Movements" OR "Tooth Up righting" OR "Minor Tooth Movement" OR "Minor Tooth Movements" OR "Tooth Intrusion" OR "Tooth Intrusions" OR "Tooth Depression" OR "Tooth Depressions" OR "Orthodontic Treatment" OR "Orthodontic Therapy" OR "Orthodontic Movement" OR "Tooth Movement".The search strategies for the other databases are shown in Appendix 1.Appendix 1:Scopus Atelvia OR "Risedronate Sodium" OR "Risedronic Acid Monosodium Salt" OR Actonel OR Risedronate OR "Bisphosphonate Risedronate Sodium" OR Bisphosphonate OR 2-(3-pyridinyl)-1-hydroxyethylidene-bisphosphonate OR 2-(

Table 1 :
General characteristics of the included studies.

Number of osteoclasts:
Group A: ovariectomy (saline i.p.).Group B: ovariectomy + risedronate (10ug/kgrisedronate dissolved in saline i.p.).Effect to relapse distance: the control had the highest relapse rate at days 14 and 21.There was a significantly less relapse movement in the treatment group on days 14 and 21 compared to control.Bis-CR500 inhibited the relapse movement more effectively than Bis-CR250 on day 21, indicating a dose dependency in the biphosphonate hydrogel application.

Table 2 :
Histological and molecular characteristics of orthodontic tooth displacement in the studies included.

Table 3 :
Impact of risedronate on OTM (study outcomes).

Table 4 :
Assessment of risk of bias in the included studies.